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D R Robinson

Publications and source records attributed to D R Robinson.

At least 37 records · Page 2Linked to original sources
PubMed1997

Correlated mutagenesis of bcl2 and hprt loci in blood lymphocytes.

In vivo measurement of human somatic mutations may be a valuable biodosimeter of exposure to carcinogens and of cancer risk. We have surveyed translocations at the bcl2 locus in B lymphocytes, and mutations at hprt in T lymphocytes, in 120 individuals with varying exposure to radon and cigarette smoke. bcl2 t(14:18) translocation is the commonest chromosomal alteration observed in non-Hodgkins lymphoma (NHL). We observed a significantly larger range of bcl2 translocation frequency (range: 0-372 x 10(-6), median: 1.9 x 10(-6)) than of hprt mutation frequency (range: 0-76.4 x 10(-6), median: 11.1 x 10(-6)), which is likely the result of clonal proliferation of deathless B cell mutants. We observed that the frequencies of these two distinct lymphocytic mutations are significantly correlated. Although some of the correlated variation is explained by age, a significant correlation of bcl2 mutagenesis persists after age adjustment. Correlated mutagenesis at distinct loci in distinct cell types could be explained by the existence of a mutator phenotype or by variation in exposure to environmental mutagens. NHL is commoner in men than in women, and our data indicate a trend toward higher bcl2 mutagenesis in males than females. There is mounting epidemiological evidence for a worldwide increase in NHL, which may have an environmental basis; molecular epidemiological analysis of bcl2 mutagenesis in exposed populations might be especially relevant to the identification of putative environmental causes. Given the relative ease of the bcl2 assay versus the hprt assay, and the consistency with which data are reproduced from laboratory to laboratory, it is likely that the bcl2 assay will be soon added to the array of assays used in human mutational surveillance.

Adolescent↗
PubMed1997

Dietary fish oil supplementation exacerbates serum sickness nephritis in mice.

The effects of fish oil (FO) on immune complex nephritis induced by bovine serum albumin (BSA) were studied in female B10.Br mice. The mice were fed an experimental fat-free diet composed of either 10% FO, safflower oil (SO), or beef tallow (BT) as a lipid source throughout the study. Proteinuria was observed in 84% of the FO group (n = 19), 53% of the SO group (n = 19) and in 48% of the BT group (n = 19; p = 0.0217 vs. FO). The FO group showed a tendency toward more severe renal histologic changes than the SO and BT groups. The levels of anti-BSA antibody and circulating BSA-anti-BSA immune complexes were significantly higher in the FO group than in the SO and in the BT groups. Avidity of the anti-BSA antibodies showed a lower tendendy in the FO group. Prostaglandin E2 and thromboxane B2 productions by the renal cortex were much lower in the FO than in the other two groups. The ratios thromboxane B2/prostaglandin E2 were higher in the FO than in the BT group. These results suggest that FO oil supplementation leads to the deterioration of BSA-induced immune complex nephritis in mice due to the altered immune responses in association with suppressed prostanoid production.

Animals↗
PubMed1997

Regulation of prostaglandin synthesis by antiinflammatory drugs.

The prostaglandins (PG), thromboxanes, and leukotrienes (LT) are potent groups of mediators derived from arachidonic acid. The functions of these compounds are numerous and involve every organ system, but their roles in physiology and pathology are not completely understood. PG and LT are important mediators of inflammatory reactions. Convincing evidence supports the hypothesis than inhibition of PG synthesis accounts for both the major therapeutic antiinflammatory and toxic side effects of the nonsteroidal antiinflammatory drugs. New research has revealed that PG are synthesized by 2 forms of the enzyme cyclooxygenase, COX-1 and COX-2. Since COX-1 generally produces PG responsible for cytoprotective functions and COX-2 produces PG in inflammatory reactions, it is a reasonable hypothesis that drugs that are selective inhibitors of COX-2 should be effective antiinflammatory agents with few toxic side effects.

Animals↗
PubMed1996

Dietary marine lipids suppress continuous expression of interleukin-1 beta gene transcription.

n-3 Polyunsaturated fatty acids abundant in marine lipids suppress certain inflammatory and immune reactions, and dietary marine lipid supplements have antiinflammatory effects in experimental and human autoimmune disease. Previous work by other investigators demonstrated that dietary marine lipid supplements suppressed production of cytokines from stimulated human peripheral blood mononuclear cells ex vivo. The present study further documents the ability of n-3 fatty acids to inhibit cytokine formation, and in part defines the mechanism of the inhibition of production of interleukin-1 beta (IL-1 beta) by dietary n-3 fatty acid. Female BALB/c mice were each fed a fat-free balanced diet to which was added either a refined fish oil (FO) preparation as a source of n-3 fatty acid, or beef tallow (BT), which consisted primarily of saturated and monoenoic fatty acids. After ingesting the experimental diets for periods ranging from 3 to 12 wk. spleen cell preparations were stimulated ex vivo with either lipopolysaccharide (LPS) or phorbol 12-myristate 13-acetate (PMA), and proIL-1 beta mRNA (IL-1 beta mRNA) was measured by northern analysis. Levels of IL-1 beta mRNA in both LPS- and PMA-stimulated cells from BT-fed mice were elevated to a greater extent than in cells from FO-fed mice, at most concentrations of LPS and PMA. Stability of LPS-stimulated mRNA levels after actinomycin D was similar for BT and FO groups, indicating that lower levels of IL-1 mRNA with FO groups was related to suppressed IL-1 gene transcription and not due to accelerated transcript degradation. Nuclear run-on transcription assays revealed a more transient expression of the IL-1 beta gene in LPS-stimulated spleen cells from FO-fed mice compared to cells from BT-fed mice. We conclude that dietary marine lipids reduce transient expression of the IL-1 beta gene in stimulated splenic monocytic cells. Preliminary results from nuclear run-on transcription assays indicate that n-3 fatty acids may not change the initial rate of gene transcription but may promote more rapid shutting down of transcription of this gene after induction than do alternative lipids.

Animals↗
PubMed1996

Non-invasive diagnosis of infarct artery patency after acute myocardial infarction by use of serial plasma troponin T concentrations: importance of measurement of peak levels.

OBJECTIVE: To confirm the validity of a previously described method for assessment of infarct artery patency involving serial measurements of creatine kinase activity by use of troponin T concentration as an independent plasma marker. DESIGN: Streptokinase (1.5 x 10(6) units) was given intravenously to 60 patients within 6 h of onset of prolonged chest pain and ST segment elevation, and blood was taken for measurement of troponin T concentration at baseline and at 1, 2, 3, 4, 8, 12, 16, 20, and 24 h after starting treatment. Coronary arteriography was performed at 2.6 (SD 0.3) h. Plasma troponin T concentration was assessed by two methods: (1) as the absolute rise between 0 and 3 h; and (2) as the proportion of the total rise (from baseline to peak) over the same period. Accuracy for prediction of infarct artery patency, assessed by receiver operating characteristic curves, was compared for both methods of assessment using troponin T and was in turn compared with previously reported results on the same patients using serial measurements of creatine kinase activity. RESULTS: Sufficient values for prediction of patency using troponin T were available in 53 patients. A rise in troponin T between 0 and 3 h to > or = 9% of peak concentration predicted angiographic patency with sensitivity of 94% and specificity of 100%. By contrast, at the optimum cutoff for absolute rate of rise (0.5 micrograms/l/h) sensitivity was only 66% and specificity 86%. Comparable figures for creatine kinase were 92% and 91% (> or = 20% of peak by 3 h) and 62% and 78% (150 IU/l/h). Receiver operating curves confirmed better predictive accuracy for proportions over absolute rates of rise for both markers (P < 0.01). CONCLUSIONS: For accurate diagnosis of infarct artery patency using plasma markers it is necessary to express the rate of rise as a proportion of the peak level. Analysed in this way, both creatine kinase and troponin T are suitable for use in randomised trials of new thrombolytic or adjuvant drugs.

Adult↗
PubMed1995

Microtubule polarity and dynamics in the control of organelle positioning, segregation, and cytokinesis in the trypanosome cell cycle.

Trypanosoma brucei has a precisely ordered microtubule cytoskeleton whose morphogenesis is central to cell cycle events such as organelle positioning, segregation, mitosis, and cytokinesis. We have defined microtubule polarity and show the + ends of the cortical microtubules to be at the posterior end of the cell. Measurements of organelle positions through the cell cycle reveal a high degree of coordinate movement and a relationship with overall cell extension. Quantitative analysis of the segregation of the replicated mitochondrial genome (the kinetoplast) by the flagellar basal bodies identifies a new G2 cell cycle event marker. The subsequent mitosis then positions one "daughter" nucleus into the gap between the segregated basal bodies/kinetoplasts. The anterior daughter nucleus maintains its position relative to the anterior of the cell, suggesting an effective yet cryptic nuclear positioning mechanism. Inhibition of microtubule dynamics by rhizoxin results in a phenomenon whereby cells, which have segregated their kinetoplasts yet are compromised in mitosis, cleave into a nucleated portion and a flagellated, anucleate, cytoplast. We term these cytoplasts "zoids" and show that they contain the posterior (new) flagellum and associated basal-body/kinetoplast complex. Examination of zoids suggests a role for the flagellum attachment zone (FAZ) in defining the position for the axis of cleavage in trypanosomes. Progression through cytokinesis, (zoid formation) while mitosis is compromised, suggests that the dependency relationships leading to the classical cell cycle check points may be altered in trypanosomes, to take account of the need to segregate two unit genomes (nuclear and mitochondrial) in this cell.

Animals↗
PubMed1995

Platelet factor 4 injection produces acute pulmonary hypertension in the awake lamb.

BACKGROUND: Reversal of heparin anticoagulation by intravenous protamine sulfate consistently produces acute pulmonary vasoconstriction mediated by the release of thromboxane in the awake lamb. Recently, recombinant platelet factor 4 (rPF4) has been cloned, expressed in Escherichia coli, and infused to reverse heparin anticoagulation in the rat, without producing adverse hemodynamic or pulmonary morphologic effects. The authors sought to learn whether intravenous administration of PF4 is devoid of side effects in the pulmonary circulation of lambs. METHODS: The authors evaluated the hemodynamic response and plasma release rates of thromboxane during intravenous challenges with heparin-rPF4 (n = 2), rPF-free carrier (n = 5), rPF4 (n = 5), rPF4 after indomethacin (n = 5), protamine (n = 5) and heparin-protamine (n = 5) in 17 awake, hemodynamically monitored lambs. Each lamb underwent up to three random challenges with a 2-h recovery period between each challenge. RESULTS: In two lambs, systemic anticoagulation with heparin followed by reversal of anticoagulation with an intravenous bolus of rPF4 (4 mg/kg) led to acute pulmonary vasoconstriction and hypertension with the release of thromboxane (peak pulmonary artery pressure [Ppa] 40 and 33 mmHg and peak plasma thromboxane B2 50 and 30 ng/ml, respectively). Intravenous administration of rPF4 (1.5 mg/kg) alone increased the Ppa from 17.2 +/- 0.7 mmHg (mean +/- SEM) at baseline to 31.2 +/- 2 mmHg at 1 min (n = 5, P < 0.05). This was associated with an increase of plasma thromboxane B2 from 0.06 +/- 0.02 to 3.96 +/- 1.21 ng/ml. Acute pulmonary vasoconstriction lasted approximately 5 min and was completely prevented by pre-treatment with oral indomethacin (10 mg/kg). Intravenous bolus administration of rPF4 carrier (n = 5) or protamine (2 mg/kg) alone (n = 5) did not induce pulmonary hypertension or the release of thromboxane. In five lambs, intravenous heparin (200 U/kg) followed by protamine (2 mg/kg) consistently produced acute pulmonary vasoconstriction and hypertension. CONCLUSIONS: Intravenous injection of human rPF4 into the awake lamb produces acute pulmonary vasoconstriction and hypertension associated with thromboxane release into circulating blood. The effects of rPF4 on the pulmonary vasculature should be evaluated in primates before rPF4 is substituted for protamine in reversing heparin anticoagulation in humans.

Animals↗
PubMed1994

The configuration of DNA replication sites within the Trypanosoma brucei kinetoplast.

The kinetoplast is a concatenated network of circular DNA molecules found in the mitochondrion of many trypanosomes. This mass of DNA is replicated in a discrete "S" phase in the cell cycle. We have tracked the incorporation of the thymidine analogue 5-bromodeoxyuridine into newly replicated DNA by immunofluorescence and novel immunogold labeling procedures. This has allowed the detection of particular sites of replicated DNA in the replicating and segregating kinetoplast. These studies provide a new method for observing kinetoplast DNA (kDNA) replication patterns at high resolution. The techniques reveal that initially the pattern of replicated DNA is antipodal and can be detected both on isolated complexes and in replicating kDNA in vivo. In Trypanosoma brucei the opposing edges of replicating kDNA never extend around the complete circumference of the network, as seen in other kinetoplastids. Furthermore, crescent-shaped labeling patterns are formed which give way to labeling of most of the replicating kDNA except the characteristic midzone. The configuration of these sites of replicated DNA molecules is different to previous studies on organisms such as Crithidia fasciculata, suggesting differences in the timing of replication of mini and maxicircles and/or organization of the replicative apparatus in the kinetoplast of the African trypanosome.

Animals↗
PubMed1993

Protective effects of anti-O polysaccharide and anti-lipid A monoclonal antibodies on pulmonary hemodynamics.

Monoclonal antibodies (MAbs) directed to endotoxin can protect in some animal models against the pathophysiological effects of endotoxin infusion. When 0.02 microgram/kg of lipopolysaccharide (LPS) derived from Escherichia coli O111:B4 was incubated in vitro for 2 h with the murine immunoglobulin G MAb, 5B10, directed against the O-polysaccharide antigenic domain of E. coli O111:B4 and then the mixture was infused into sheep, we noted significant protection. The second temperature peak was decreased (P < 0.05 vs. LPS control). The acute pulmonary arterial pressure elevation was diminished (mean peak pulmonary arterial pressure 23.2 +/- 2.5 mmHg, P < 0.05 vs. LPS control), and the peak plasma thromboxane B2 level was reduced (mean peak thromboxane B2 level 0.50 +/- 0.15 ng/ml, P < 0.05 vs. LPS control). In contrast, preincubation of the LPS with a human immunoglobulin M MAb, HA-1A, directed against the core glycolipid of the LPS molecule provided no protective effects in this sheep model. This finding is in agreement with recent studies reporting HA-1A may bind to antibiotic-treated bacteria but not to purified smooth LPS.

Animals↗
PubMed1993

Protective effects of E5, an antiendotoxin monoclonal antibody, in the ovine pulmonary circulation.

The cross-protective effects of a murine immunoglobulin M monoclonal antilipid A antibody (E5 MAb) were tested by challenging awake sheep with mixtures of in vitro incubated E5 MAb (0.02 mg/kg) with lipopolysaccharide (LPS, 0.02 micrograms/kg) derived from Escherichia coli O111:B4, E. coli O55:B5, or Serratia marcescens. Intravenous infusion of these LPS preparations without antibody into awake sheep produced a similar pattern of fever, leukopenia, plasma thromboxane B2 (TxB2) release, and acute pulmonary vasoconstriction with pulmonary hypertension. The addition of MAb E5 to LPS from E. coli O111:B4 reduced these responses to the LPS in a fashion comparable to that achieved with an MAb specific to the E. coli O111:B4 O-side chain. Incubation of LPS derived from E. coli O55:B5 with the E5 MAb only slightly diminished acute pulmonary hypertension, the delayed temperature increase, and the degree of leukopenia (all P = NS) but reduced the mean peak TxB2 at 60 min (P < 0.05) compared with a control infusion of E. coli O55:B5 LPS. We were unable to demonstrate any protective effects on the pulmonary circulation from incubating E5 with LPS derived from S. marcescens. Preincubation of B55 MAb (a murine immunoglobulin M MAb directed against a human milk fat globulin), the control antibody, with LPS from E. coli 0111:B4 decreased the mean peak TxB2 but had no effect on the other parameters. We conclude that incubating E5 with LPS protects the pulmonary circulation of sheep from challenge with LPS derived from the parent E. coli strain. There were trends toward protection by E5 against LPS from 055:B5 E. coli, but these did not reach statistical significance.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Dietary omega-3 polyunsaturated fatty acids inhibit phosphoinositide formation and chemotaxis in neutrophils.

Earlier studies demonstrated that dietary omega-3 polyunsaturated fatty acid (PUFA) supplementation attenuates the chemotactic response of neutrophils and the generation of leukotriene (LT) B4 by neutrophils stimulated with calcium ionophore; however, the mechanisms and relationship of these effects were not examined. Neutrophils and monocytes from eight healthy individuals were examined before and after 3 and 10 wk of dietary supplementation with 20 g SuperEPA daily, which provides 9.4 g eicosapentaenoic acid (EPA) and 5 g docosahexaenoic acid. The maximal neutrophil chemotactic response to LTB4, assessed in Boyden microchambers, decreased by 69% after 3 wk and by 93% after 10 wk from prediet values. The formation of [3H]inositol tris-phosphate (IP3) by [3H]inositol-labeled neutrophils stimulated by LTB4 decreased by 71% after 3 wk (0.033 +/- 0.013% [3H] release, mean +/- SEM) and by 90% after 10 wk (0.011 +/- 0.011%) from predict values (0.114 +/- 0.030%) as quantitated by beta-scintillation counting after resolution on HPLC. LTB4-stimulated neutrophil chemotaxis and IP3 formation correlated significantly (P < 0.0001); each response correlated closely and negatively with the EPA content of the neutrophil phosphatidylinositol (PI) pool (P = 0.0003 and P = 0.0005, respectively). Neither the affinities and densities of the high and low affinity LTB4 receptors on neutrophils nor LTB4-mediated diglyceride formation changed appreciably during the study. Similar results were observed in neutrophils activated with platelet-activating factor (PAF). The summed formation of LTB4 plus LTB5 was selectively inhibited in calcium ionophore-stimulated neutrophils and was also inhibited in zymosan-stimulated neutrophils. The inhibition of the summed formation of LTB4 plus LTB5 in calcium ionophore-stimulated neutrophils and in zymosan-stimulated neutrophils did not correlate significantly with the EPA content of the PI pool. The data indicate that dietary omega-3 PUFA supplementation inhibits the autoamplification of the neutrophil inflammatory response by decreasing LTB4 formation through the inactivation of the LTA epoxide hydrolase and independently by inhibiting LTB4- (and PAF) stimulated chemotaxis by attenuating the formation of IP3 by the PI-selective phospholipase C. This is the initial demonstration that dietary omega-3 PUFA supplementation can suppress signal transduction at the level of the PI-specific phospholipase C in humans.

Adult↗
PubMed1993

Modification of spleen phospholipid fatty acid composition by dietary fish oil and by n-3 fatty acid ethyl esters.

We have compared the effects of diets containing purified ethyl esters of either eicosapentaenoic acid, docosahexaenoic acid, or a mixture of both of these compounds, with diets containing either purified fish oil or beef tallow on spleen phospholipid fatty acid composition. Autoimmune mice, the (NZB x NZW)F1 strain, were fed with experimental diets for 14 weeks, after which spleen phospholipids were extracted and separated into classes by HPLC, and the alkenylacyl, alkylacyl, and diacyl subclasses of glycerylphosphatidylethanolamine and glycerylphosphatidylcholine were resolved as their benzoyl esters by HPLC. Fatty acids were analyzed by capillary gas-liquid chromatography of their methyl esters. Each of the marine lipid diets suppressed n-6 fatty acids and elevated n-3 fatty acids in all phospholipids. The eicosapentaenoic acid ethyl ester diets led to high levels of eicosapentaenoic acid and docosapentaenoic acid (C22:5n-3), but little or no increase in docosahexaenoic acid. The docosahexaenoic acid ethyl ester diets elevated docosahexaenoic acid, docosapentaenoic acid, and eicosapentaenoic acid in all phospholipids, indicating that extensive retroconversion of 22 carbon n-3 fatty acids had occurred. These results document changes in the fatty acid composition of mammalian phospholipids that are induced by dietary fish oil triglycerides and by dietary long chain n-3 fatty acid ethyl esters.

Animals↗
PubMed1993

Suppression of autoimmune disease by dietary n-3 fatty acids.

Previous studies have demonstrated that dietary fish oil preparations have anti-inflammatory effects in humans and in experimental animals, but the individual components of fish oils that are responsible for their anti-inflammatory effects have not been documented. We therefore investigated in (NZB x NZW)F1 mice, a model for human systemic lupus erythematosus, the effects of diets containing ethyl esters of two purified n-3 fatty acids, eicosapentaenoic acid (EPA-E) and docosahexaenoic acid (DHA-E), a refined fish oil triglyceride (FO) which contained 55% n-3 fatty acids, and beef tallow (BT) which contains no n-3 fatty acids. The diets were initiated prior to the development of overt renal disease at age 22 weeks, and continued for 14 weeks. The extent of the renal disease was quantified by light microscopy and by proteinuria. Diets containing either 10 wt% FO, 10% EPA-E, or 6% or 10% DHA-E alleviated the severity of the renal disease, compared to the BT diet, whereas diets containing either 3% or 6% EPA-E or 3% DHA-E were less effective. Two diets containing approximately 3:1 mixtures of EPA-E and DHA-E alleviated the renal disease to a greater extent than expected for either of these fatty acids given singly. We believe that these experiments provide the first demonstration of anti-inflammatory effects of individual dietary n-3 fatty acids. The results also indicate that the anti-inflammatory effects of fish oils depend on synergistic effects of at least two n-3 fatty acids.

Animals↗
PubMed1992

Effects of naproxen on renal function in older patients with mild to moderate renal dysfunction.

We have evaluated 45 elderly patients with both musculoskeletal problems and mild to moderate renal dysfunction. We treated these patients with a non-steroidal anti-inflammatory drug (NSAID) for 2 weeks. The serum creatinine, urinary creatinine clearance and blood pressure were monitored before and after therapy. In some patients serum levels of thromboxane B2 (TxB2) and the urinary prostaglandins E2 (PGE2) and I2 (prostacyclin) measured as 6-keto-PGF1 alpha were also monitored before and after therapy and correlated with the clinical measurements. This study has demonstrated that in the entire patient group, the trial drug was tolerated extremely well. There were no changes in the serum creatinine or in the urinary creatinine clearance after 2 weeks of therapy. There was also no change in the early morning diastolic blood pressure. In the 11 patients in whom the serum and urinary prostaglandins were measured, the serum thromboxane levels fell with therapy to a level of 1.5% of the initial value. The urinary levels of PGE2 also fell but not to the same degree. The urinary PGE2 levels fell to 28% of the baseline values. There was no significant change in the levels of urinary 6-keto-PGF1 alpha (prostacyclin). These observations suggest that prostacyclin may be the important prostaglandin in maintaining normal renal haemodynamics when patients are treated with NSAIDs.

Aged↗
PubMed1991

Basal body movements as a mechanism for mitochondrial genome segregation in the trypanosome cell cycle.

The mitochondrial genome of Trypanosoma brucei is organized in the form of a complex catenated network of circular DNA molecules. This mass of DNA, known as the kinetoplast, is present at a unique site in the single mitochondrion, and is replicated in a discrete, periodic S phase of the cell cycle. The single-copy nature of the kinetoplast suggests that there is a mechanism ensuring segregation fidelity of replicated copies to each daughter cell. Historically, speculation regarding the nature of this mechanism has often attributed significance to the close association between the kinetoplast and the flagellum basal body. We provide here direct evidence that this mitochondrial DNA complex is indeed linked to the basal body, and segregation of the kinetoplast DNA is dependent on a microtubule-mediated separation of the new and old flagellar basal bodies during the cell cycle. This unique system may represent the remnants of an evolutionarily archaic mechanism for genome segregation.

Animals↗
PubMed1991

Inhaled nitric oxide. A selective pulmonary vasodilator of heparin-protamine vasoconstriction in sheep.

Nitric oxide (NO) has recently been discovered to be an important endothelium-derived relaxing factor and produces profound relaxation of vascular smooth muscle. To learn if NO could be a potent and selective pulmonary vasodilator, NO was inhaled by 16 awake lambs in an attempt to reduce the increase in pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) induced by either the infusion of an exogenous pulmonary vasoconstrictor (the thromboxane analog U46619) or the endogenous release of thromboxane that occurs during the neutralization of heparin anticoagulation by protamine sulfate. Inhaling greater than or equal to 40 ppm of NO during a continuous U46619 infusion returned the PAP to a normal value, without affecting systemic blood pressure or vascular resistance. Pretreatment with the cyclooxygenase inhibitor indomethacin before infusing U46619 did not reduce the pulmonary vasodilatory effect of inhaled NO, and we conclude that the dilatory effect of NO on the lung's circulation is independent of cyclooxygenase products such as prostacyclin. Continuously inhaling NO at 180 ppm did not significantly reduce the mean peak thromboxane B2 concentration at 1 min after protamine injection; however, the mean values of pulmonary hypertension and vasoconstriction at 1 min were markedly reduced below the levels in untreated heparin-protamine reactions. Breathing NO at lower concentrations (40-80 ppm) did not decrease the mean peak PAP and PVR at 1 min after protamine but decreased the PAP and PVR values at 2, 3, and 5 min below those of control heparin-protamine reactions. Intravenous infusion of nitroprusside completely prevented the transient increase of PAP and PVR during the heparin-protamine reaction; however, marked concomitant systemic vasodilation occurred. Inhaled NO is a selective pulmonary vasodilator that can prevent thromboxane-induced pulmonary hypertension during the heparin-protamine reaction in lambs and can do so without causing systemic vasodilation.

Animals↗